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Delay in Treatment Intensification Increases the
Risks of Cardiovascular Events in Patients With
Type 2 Diabetes
Sanjoy K Paul; Kerenaftali Klein; Brian L Thorsted; Michael L Wolden; Kamlesh Khunti
Cardiovasc Diabetol. 2015;14(100)
Abstract
Background: The aim of the study was to evaluate the effect of delay in treatment intensification (IT; clinical inertia) in
conjunction with glycaemic burden on the risk of macrovascular events (CVE) in type 2 diabetes (T2DM) patients.
Methods: A retrospective cohort study was carried out using United Kingdom Clinical Practice Research Datalink, including
T2DM patients diagnosed from 1990 with followup data available until 2012.
Results: In the cohort of 105,477 patients mean HbA1c was 8.1% (65 mmol/mol) at diagnosis, 11% had a history of
cardiovascular disease, and 7.1% experienced at least one CVE during 5.3 years of median followup. In patients with HbA1c
consistently above 7/7.5% (53/58 mmol/mol, n = 23,101/11,281) during 2 years post diagnosis, 26/22% never received any IT.
Compared to patients with HbA1c <7% (<53 mmol/mol), in patients with HbA1c ≥7% (≥53 mmol/mol), a 1 year delay in receiving
IT was associated with significantly increased risk of MI, stroke, HF and composite CVE by 67% (HR CI: 1.39, 2.01), 51% (HR CI:
1.25, 1.83), 64% (HR CI: 1.40, 1.91) and 62% (HR CI: 1.46, 1.80) respectively. One year delay in IT in interaction with HbA1c
above 7.5% (58 mmol/mol) was also associated with similar increased risk of CVE.
Conclusions: Among patients with newly diagnosed T2DM, 22% remained under poor glycaemic control over 2 years, and 26%
never received IT. Delay in IT by 1 year in conjunction with poor glycaemic control significantly increased the risk of MI, HF, stroke
and composite CVE.
Background
Currently 8.3% of adults worldwide are estimated to have diabetes.[1] The risk of cardiovascular complications has been related to
glycaemia in patients with type 2 diabetes mellitus (T2DM). Randomised controlled trials have conclusively demonstrated that the
risk of microvascular complications can be reduced by intensive glycaemic control in patients with T2DM.[2–4] However, there are
controversies regarding the benefits of intensive glucose control [HbA1c <7% (53 mmol/mol)] on macrovascular events (CVE), as
some of the large trials have failed to show any significant reduction in CVE.[4,5] The ACCORD trial failed to show any benefit of
intensive glucose lowering on CVE, although the haemoglobin A1c (HbA1c) level was reduced to 6.4% (46.4 mmol/mol) in the
intensive treatment arm compared to HbA1c level of 7.5% (58.5 mmol/mol) in the standard treatment arm.[6] The primary care
based randomised trial ADDITION reported only a small, nonsignificant reduction in the incidence of CVE and death associated
with early intensive management of the disease.[7] However, the UKPDS Post Trial Monitoring Study demonstrated that intensive
glucose control starting at the time of diagnosis of diabetes could be associated with a significantly decreased risk of myocardial
infarction (MI) and death from any cause.[8] Also, the metaanalysis of four large cardiovascular outcome trials in patients with
T2DM revealed that tighter glycaemic control was associated with 9% reduction in risk of major cardiovascular events.[9]
However, tight glycaemic control was not associated with reduced mortality.
Glycaemic management in patients with T2DM has become increasingly complex, and in some cases controversial, with a
widening classes of pharmacological agents now available.[10–12] Based on the individual characteristics of the patients, step
wise lifestyle and pharmacological approaches have been suggested by international guidelines for better glycaemic
management in patients with T2DM.[13–15]
The American Diabetes Association guidelines recommend starting metformin alongside lifestyle modifications at diagnosis,
aiming for a HbA1c target of <7% (<53 mmol/mol).[15] Additional oral antidiabetes drugs (OADs) may be added if the HbA1c
continues to remain above the recommended target of 6.5% (48 mmol/mol), and if HbA1c reaches ≥7.5% (≥58 mmol/mol), further
intensification including the use of insulin is recommended.[13,16] The intensification of antidiabetes therapies also depends on
individual patient's characteristics including age, comorbidities, the risk of hypoglycaemia, and provider and patient's preferences.
[13] However, a high proportion of people with T2DM fail to reach the recommended glycaemic targets for a considerable period of
time post diagnosis of diabetes (glycaemic burden).[17–21] Among those with poor glycaemic control [HbA1c ≥7% (≥53
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time post diagnosis of diabetes (glycaemic burden).[17–21] Among those with poor glycaemic control [HbA1c ≥7% (≥53
mmol/mol)], an overwhelmingly large proportion of people do not receive intensified treatment in time. This "delay in treatment
intensification", also termed as clinical inertia, has been discussed by some studies.[17–21] A recent study based on 80,000
patients with T2DM from the United Kingdom primary care system reported that the average time to intensification to two oral anti
diabetes drugs (OADs) from one OAD among patients with HbA1c above 7% (53 mmol/mol) was about 3 years.[21] The aspects
of glycaemic variability and treatment quality indicators and their association with macrovascular risk were evaluated by Penno et
al.[22] and Sidorenkov et al.,[23] respectively. Asche et al.[24] evaluated the clinical and economic benefits of early intensification of
treatment with insulin in patients with T2DM, and reported significant benefits in terms of glycaemic management.
While studies have reported the realworld scenario in terms of intensification of treatments for hyperglycaemia among patients
with poorly controlled glycaemia, the possible effect of delay in treatment intensification in conjunction with the dynamic changes
in glycaemic control on the vascular risk factors, has not yet been studied to the best of our knowledge. The aims of this
retrospective cohort study were to (1) explore the glycaemic control over 2 years post diagnosis of diabetes in relation to
treatment intensification, and (2) evaluate the effect of the delay in treatment intensification in conjunction with guideline
recommended glycaemic control on the of risk of MI, heart failure (HF), stroke, and composite of these three CVE.
Methods
Data Source
The data for this retrospective cohort study was extracted from the United Kingdom Clinical Practice Research Datalink (CPRD),
which is representative of the United Kingdom general population.[25–27] All information collected in the CPRD has been
subjected to validation studies and been proven to contain consistent and highquality data.[26,28]
Data were extracted from CPRD with a first identifiable record of diagnosis code for T2DM covering period from January 1990
with followup data to December 2012, with maximum possible followup time of 23 years. The confirmation for the incident
diagnosis of T2DM was based on Read/Oxford Medical Information System Codes,[29] supported by rigorous classification
techniques.[30,31]
The following information was extracted: age, gender, smoking status (defined as current, ex or never smoker), body mass index
(BMI), HbA1c, history of cardiovascular and renal diseases before the diagnosis of diabetes, and clinical events during followup,
including cardiovascular diseases (MI, HF, stroke and coronary heart diseases), atherosclerosis, diabetic neuropathy, and renal
complications, along with dates of events. Detailed information on OADs and insulin along with antihypertensive and cardio
protective medications (including use of ACE inhibitor, Beta Blocker, Statin and other concomitant medications) were obtained
from prescriptions along with dates. The study cohort (n = 105,477) was based under the conditions: (1) read code for T2DM and
at least two prescriptions for any OAD or insulin (as recorded in the primary care system) within 6 months of date of diagnosis of
T2DM (prescription provided and recorded by general practice), (2) age ≥18 years at index date (date of diagnosis of T2DM), (3)
complete information on age, sex, smoking status at index date, (4) a measure of HbA1c available within a 3month window of the
index date (HbA1c measured within 3 months before the date of first diagnosis code recorded), (5) minimum 2 years of followup
before the occurrence of any CVE post diagnosis of diabetes, (6) availability of dates of prescriptions longitudinally for anti
diabetes drugs, (7) completeness of dates for all CVEs during post diagnosis followup. Choice of this cohort of patients with new
diagnosis of T2DM ensures censoring for CVE in the first 2 years post diagnosis of diabetes, and 2 years window for treatment
intensification with the availability of data on glycaemic control.
Clinical comorbidities prior to diagnosis of diabetes, including cardiovascular and renal diseases, were coded as present if they
were diagnosed at any point between entry into CPRD and the index date. The clinical and laboratory measures were arranged
longitudinally on the basis of 6monthly windows. The 6month windows were defined progressive from the index date, with 180
days immediately post index date defining first followup window.
The study was approved by the Independent Scientific Advisory Committee (Protocol no 13_062R2).
Statistical Methods
Treatment intensification (IT) was defined in two ways: (1) adding a second OAD (OAD2) or (2) adding insulin to the first OAD
(OAD + INS). Time to IT was calculated by subtracting the index date from the first date of IT. The subjects who did not belong to
OAD2 or OAD + INS groups were defined as "never intensified" category.
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Missing HbA1c data (about 9% missing over 24 months post diagnosis) at 6monthly window were imputed using multiple
imputation technique (Bayesian MCMC approach).[32,33] The consistency of the imputed data with the original HbA1c data was
verified. Adequate checks were in place to ensure that patients were not lost to followup for imputing missing values during 2
years post diagnosis. Patients were categorized by HbA1c below or above 7% (53 mmol/mol) and 7.5% (58 mmol/mol)
consistently over 1 and 2 years post diagnosis to identify poor glycaemic control.
The composite CVE was based on the occurrence of either of MI, HF or stroke. To evaluate the effect of delay in IT on events,
only those vascular events were considered which occurred after the time of first intensification (OAD2 or OAD + INS), apart from
the condition of no occurrence of CVE during first 2 years post diagnosis of diabetes (to ensure minimum exposure time of 2
years). In this context, the "time to" individual events were calculated by subtracting the first event date (as appropriate) from the
date when intensified treatment started. The analysis set for cardiovascular risk analysis included only those belonging to OAD2
or OAD + INS categories.
As time to treatment intensification (TTIT) is highly likely to be interacted with the glycaemic control over time, the interaction of
TTIT with HbA1c categories over time was evaluated in terms of cardiovascular risks. To evaluate the interaction effect we
constructed the following four groups: reference group—TTIT <12 months and HbA1c <7% (<53 mmol/mol) (consistently <7%
over 12 months post diagnosis); group 1—TTIT ≥12 months and HbA1c ≥7% (≥53 mmol/mol); group 2—TTIT <12 months and
HbA1c ≥7% (≥53 mmol/mol); group 3—TTIT ≥12 months and HbA1c <7% (<53 mmol/mol). The Group 1 reflects both clinical
inertia and glycaemic burden together, while Group 2 reflects only the glycaemic burden. Multivariate Cox regression models were
used to evaluate the effect of delay in IT in conjunction with poor glycaemic control consistently over 1 year post diagnosis,
adjusting for age and HbA1c at diagnosis of diabetes, sex, smoking status, use of cardioprotective medications (Statin, ACE/ARB
and Beta Blocker), any renal disease during followup, and the history of CVD before diagnosis of diabetes. The proportionality
assumption in the models was tested, and stratified models were fitted with the quartiles of age at diagnosis of diabetes as the
stratifying factor. Separate analyses were also conducted for patients with and without the history of CVE. Additional multivariate
Cox regression models were also fitted with incomplete information on BMI, systolic blood pressure, LDLcholesterol and total
cholesterol at diagnosis (about 62,000 patients).
To evaluate the possible lack of treatment intensification in older patients (age >70 years at diagnosis of diabetes) and in patients
with history of CVD and renal diseases, logistic regression models were fitted. The odds ratios (OR) and their 95% confidence
intervals were presented. The likelihood of receiving intensified treatment in poorly controlled patients by categories based on
time windows of diagnosis was also evaluated.
Results
In the cohort of 105,477 patients: 56% were male, 62% current or exsmokers, mean (SD) age at diagnosis of 61 (13) years, and
11% (n = 11,955) had history of CVD before the diagnosis of diabetes (). The distribution of HbA1c was highly skewed at
diagnosis of diabetes, with mean (SD) and median (IQR) levels of 8.1 (2.2)% (65 mmol/mol) and 7.4 (6.5, 9.3)% [57 (48, 78)
mmol/mol], respectively, and 62% patients had HbA1c ≥7% (≥53 mmol/mol) at diagnosis.
Table 1. Descriptive statistics on study parameters at diagnosis of diabetes and at followup
Patients by year of diagnosis a
Smoking status a
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HbA1c at diagnosis (mmol/mol)b 66 62 65
HbA1C ≥7% (≥53 mmol/mol) post diagnosisa
CVE during followupa
Renal diseasea
Medication a
In the study cohort 48,036 patients (46%) received intensified treatment (IT) during followup. Among those who received IT, the
proportions with time to IT (TTIT) <6 months, <1 year, and <2 years were 26, 36, and 53%, respectively. The overall median/mean
time (months) to receiving IT, at least 2 OADs (2OADs) and at least 3 antidiabetes drugs (3ADDs) were 21/29, 22/29, and 43/48,
respectively.
The Clinical Inertia and Glycaemic Burden
The 6monthly trajectory of HbA1c over 2 years post diagnosis of diabetes, by the categories of TTIT, is presented in Fig. 1.
Patients who did not receive any IT during followup had their average glycaemic level below 7% (53 mmol/mol) during 2 years
post diagnosis, starting with an average HbA1c level of 7.4% (57 mmol/mol) at diagnosis (Fig. 1a). However, patients who receive
intensified treatment continued to have average HbA1c trajectory level around 7.5% (58 mmol/mol) during 2 years post diagnosis
irrespective of the time of treatment intensification (Fig. 1a). Among patients with HbA1c ≥7% (≥53 mmol/mol) consistently during
1/2 year post diagnosis, 29/26% never received any IT during followup. Among those with HbA1c ≥7% (≥53 mmol/mol) during 1
year post diagnosis, only 40% received IT before 12 months, and the median time to IT was 16 months (). In patients with HbA1c
≥7% (≥53 mmol/mol) consistently during 2 years post diagnosis, only 64% patients received IT before 2 years of diagnosis, and
the median time to IT or receiving at least two OADs was 17 months (mean = 23 months).
Table 2. Proportions of patients with HbA1c above 7 and 7.5% consistently during 1 year and 2 years post diagnosis of
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diabetes by categories of time to intensified treatment, and the median (IQR) months to treatment intensifications from
diagnosis of diabetes for various classifications of Hba1c trajectory
n (%) by time to intensified treatment Time to intensification median (IQR),
categories months
Time to Time to 2 Time to 3
<6 months <1 year <2 years
IT OADs ADDs
HbA1c ≥7% (≥53 mmol/mol)
Consistently during 2
4,696 (28) 6,864 (40) 10,904 (64) 17 (5, 31) 17 (6, 32) 36 (20, 58)
years
HbA1c ≥7.5% (≥58 mmol/mol)
Consistently during 2
2,774 (32) 3,999 (46) 6,171 (70) 14 (4, 27) 15 (5, 28) 31 (18, 52)
years
Figure 1.
Sixmonthly measure of HbA1c (mean and 95% CI) from diagnosis to 2 years, by a patients with and without intensified treatment
during followup, b by patients receiving treatment intensification before or after 12 months of diagnosis.
Among patients with HbA1c ≥7.5% (≥58 mmol/mol) consistently during 1/2 year post diagnosis, 23/22% never received any IT
during followup. Among those with HbA1c ≥7.5% (≥58 mmol/mol) during 1 year post diagnosis, only 46% received IT before 1
year, and the median time to IT or receiving at least two OADs was 14 months (mean 20 months). In patients with HbA1c ≥7.5%
(≥58 mmol/mol) consistently during 2 years, 70% received IT within 2 years post diagnosis. The median/mean months to IT and 3
ADDs in this group were 14/20 and 31/38 months, respectively.
The distribution of patients with diagnosis of diabetes over different time periods from 1990 to 2012 are presented in . The
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average HbA1c at diagnosis in patients who were diagnosed before 2005, between 2005 and 2009 and from January 2010
onwards were 8.37, 8.02 and 7.81%, respectively, with similar standard deviation of 2.2. Among patients with HbA1c above 7.5%
(58 mmol/mol) consistently over 1 year post diagnosis of diabetes, adjusting for age and baseline HbA1c, patients diagnosed
between 2005 and 2009 and from January 2010 onwards were 46% and 139% more likely to receive intensified treatment,
compared to those who were diagnosed prior to January 2000.
Table 1. Descriptive statistics on study parameters at diagnosis of diabetes and at followup
Patients by year of diagnosis a
Smoking status a
HbA1c at diagnosis (mmol/mol)b 66 62 65
HbA1C ≥7% (≥53 mmol/mol) post diagnosisa
CVE during followupa
Renal diseasea
Medication a
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Intensified treatment 44,042 (45) 4,012 (56) 48,036 (46)
aN (%).
bMean (SD).
cMedian (IQR).
Among patients with HbA1c above 7.5% (58 mmol/mol) consistently for 1 year from diagnosis of diabetes—patients older than 70
years at diagnosis, with renal disease and with cardiovascular disease were 30% (95% CI of odds ratio: 0.63, 0.76), 13% (95% CI
of odds ratio: 0.79, 0.96) and 50% (95% CI of odds ratio: 0.45, 0.57) less likely to receive intensified treatment during followup,
respectively.
Effect of Clinical Inertia on Cardiovascular Risk
During 5.3 years of median followup, the proportions of patients who experienced at least one episode of MI, stroke, HF, and any
of composite CVE were 2.3, 3.0, 2.2 and 6.8%, respectively. Among those with a history of CVD (n = 11,955), these proportions
were 4.8, 7.5, 4.1 and 14.4%, respectively. Patients with HbA1c above 7% (53 mmol/mol) consistently during 1 year post
diagnosis had significantly higher rate (per 1,000 person years) of composite CVE [rate (95% CI) for HbA1c ≥7% (≥53 mmol/mol)
vs <7% (<53 mmol/mol): 1.15 (1.10, 1.20) vs 1.04 (1.01, 1.08)]. The event rates were similar for those with HbA1c ≥7.5% (≥58
mmol/mol) during 1 year post diagnosis.
Among all patients, compared to patients with HbA1c below 7% (53 mmol/mol) who received IT before 1 year of diagnosis,
patients with HbA1c ≥7% (≥53 mmol/mol) not receiving IT within a year had significantly increased risk of MI, HF, stroke and
composite CVE significantly by 67, 64, 51 and 62%, respectively, after adjusting for various confounding factors (all p < 0.01, ).
Among patients without history of any CVD (n = 93,522), a delay in treatment intensification by 12 months [in conjunction with
poor HbA1c level above 7% (53 mmol/mol)] was associated with significantly increased risks for MI, HF, stroke and composite
CVE by 80% (HR CI: 1.45, 2.22), 63% (HR CI: 1.36, 1.96), 50% (HR CI: 1.22, 1.84) and 64% (HR CI: 1.45, 1.85), respectively (all
p < 0.01). Delay in treatment intensification by 12 months in interaction with poor HbA1c level above 7.5% (58 mmol/mol) during 1
year post diagnosis also had similar increased risks for CVE. Among patients with history of CVD prior to diagnosis of diabetes (n
= 11,955), delay in treatment intensification in conjunction with poor glycaemic control was also significantly associated with
increased risk of HF and composite CVE, but not with MI or stroke ().
Table 3. Hazard ratios (95% CI) associated with delays in treatment intensification by 1 year in interaction with poor glycaemic
control [HbA1C ≥7% (≥53 mmol/mol) and HbA1C ≥7.5% (≥58 mmol/mol)] consistently during 1 year post diagnosis of diabetes
for cardiovascular events
MI
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.37 (1.09, 1.72) <0.01 1.21 (0.81, 1.82) 0.36 1.32 (1.08, 1.61) <0.01
year
B: IT after 1
1.80 (1.45, 2.22) <0.01 1.34 (0.91, 1.96) 0.13 1.67 (1.39, 2.01) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.59 (1.27, 1.99) <0.01 1.12 (0.73, 1.71) 0.62 1.47 (1.20, 1.79) <0.01
year
B: IT after 1
1.56 (1.24, 1.97) <0.01 1.42 (0.95, 2.14) 0.09 1.52 (1.24, 1.86) <0.01
year
HF
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
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year 1.14 (0.94, 1.40) 0.19 1.52 (1.09, 2.12) 0.015 1.23 (1.04, 1.46) 0.017
B: IT after 1
1.63 (1.36, 1.96) <0.01 1.66 (1.21, 2.27) <0.01 1.64 (1.40, 1.91) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.07, 1.62) <0.01 1.52 (1.08, 2.13) 0.016 1.37 (1.15, 1.63) <0.01
year
B: IT after 1
1.61 (1.32, 1.97) <0.01 1.50 (1.06, 2.12) 0.021 1.58 (1.33, 1.88) <0.01
year
Stroke
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.28 (1.03, 1.60) 0.025 1.80 (1.10, 2.95) 0.019 1.36 (1.12, 1.66) <0.01
year
B: IT after 1
1.50 (1.22, 1.84) <0.01 1.60 (0.98, 2.60) 0.06 1.51 (1.25, 1.83) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.27 (1.01, 1.59) 0.040 1.89 (1.16, 3.06) 0.010 1.36 (1.11, 1.67) <0.01
year
B: IT after 1
1.37 (1.09, 1.71) <0.01 1.34 (0.78, 2.30) 0.28 1.36 (1.11, 1.67) <0.01
year
Any CVE
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.22 (1.07, 1.38) <0.01 1.36 (1.06, 1.74) 0.015 1.24 (1.11, 1.40) <0.01
year
B: IT after 1
1.64 (1.45, 1.85) <0.01 1.57 (1.25, 1.98) <0.01 1.62 (1.46, 1.80) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.15, 1.50) <0.01 1.40 (1.09, 1.81) <0.01 1.33 (1.19, 1.50) <0.01
year
B: IT after 1
1.50 (1.32, 1.71) <0.01 1.50 (1.17, 1.94) <0.01 1.50 (1.33, 1.68) <0.01
year
The reference group was those with TTIT <12 months and HbA1c <7 or 7.5% (<53 or 58 mmol/mol). A: TTIT <12 months and
HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol), B: TTIT ≥12 months and HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol). Analyses are based
on multivariate Coxregression models, with contrast matrix to evaluate the effect of delay in treatment intensification in
conjunction higher and lower levels of HbA1c at 7 and 7.5% cut offs (53 and 58 mmol/mol).
Table 3. Hazard ratios (95% CI) associated with delays in treatment intensification by 1 year in interaction with poor glycaemic
control [HbA1C ≥7% (≥53 mmol/mol) and HbA1C ≥7.5% (≥58 mmol/mol)] consistently during 1 year post diagnosis of diabetes
for cardiovascular events
MI
With HbA1C ≥7% (≥53 mmol/mol)
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A: IT within 1 1.37 (1.09, 1.72) <0.01 1.21 (0.81, 1.82) 0.36 1.32 (1.08, 1.61) <0.01
year
B: IT after 1
1.80 (1.45, 2.22) <0.01 1.34 (0.91, 1.96) 0.13 1.67 (1.39, 2.01) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.59 (1.27, 1.99) <0.01 1.12 (0.73, 1.71) 0.62 1.47 (1.20, 1.79) <0.01
year
B: IT after 1
1.56 (1.24, 1.97) <0.01 1.42 (0.95, 2.14) 0.09 1.52 (1.24, 1.86) <0.01
year
HF
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.14 (0.94, 1.40) 0.19 1.52 (1.09, 2.12) 0.015 1.23 (1.04, 1.46) 0.017
year
B: IT after 1
1.63 (1.36, 1.96) <0.01 1.66 (1.21, 2.27) <0.01 1.64 (1.40, 1.91) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.07, 1.62) <0.01 1.52 (1.08, 2.13) 0.016 1.37 (1.15, 1.63) <0.01
year
B: IT after 1
1.61 (1.32, 1.97) <0.01 1.50 (1.06, 2.12) 0.021 1.58 (1.33, 1.88) <0.01
year
Stroke
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.28 (1.03, 1.60) 0.025 1.80 (1.10, 2.95) 0.019 1.36 (1.12, 1.66) <0.01
year
B: IT after 1
1.50 (1.22, 1.84) <0.01 1.60 (0.98, 2.60) 0.06 1.51 (1.25, 1.83) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.27 (1.01, 1.59) 0.040 1.89 (1.16, 3.06) 0.010 1.36 (1.11, 1.67) <0.01
year
B: IT after 1
1.37 (1.09, 1.71) <0.01 1.34 (0.78, 2.30) 0.28 1.36 (1.11, 1.67) <0.01
year
Any CVE
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.22 (1.07, 1.38) <0.01 1.36 (1.06, 1.74) 0.015 1.24 (1.11, 1.40) <0.01
year
B: IT after 1
1.64 (1.45, 1.85) <0.01 1.57 (1.25, 1.98) <0.01 1.62 (1.46, 1.80) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.15, 1.50) <0.01 1.40 (1.09, 1.81) <0.01 1.33 (1.19, 1.50) <0.01
year
B: IT after 1
1.50 (1.32, 1.71) <0.01 1.50 (1.17, 1.94) <0.01 1.50 (1.33, 1.68) <0.01
year
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The reference group was those with TTIT <12 months and HbA1c <7 or 7.5% (<53 or 58 mmol/mol). A: TTIT <12 months and
HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol), B: TTIT ≥12 months and HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol). Analyses are based
on multivariate Coxregression models, with contrast matrix to evaluate the effect of delay in treatment intensification in
conjunction higher and lower levels of HbA1c at 7 and 7.5% cut offs (53 and 58 mmol/mol).
Among patients with HbA1c above 7% (53 mmol/mol) consistently during 2 years post diagnosis (n = 23,101), patients who did
not receive intensified treatment had 82% (HR CI: 1.67, 2.10) increased risk of composite CVE. The risk estimates were similar for
patients with and without history of cardiovascular diseases. These estimates were obtained after adjusting for all factors
mentioned in the method section, except any adjustment for HbA1c levels.
Irrespective of glycaemic control, failure to intensify antihyperglycaemic treatments was associated with 42% (HR CI: 1.21, 1.66)
and 48% (HR CI: 1.36, 1.61) significantly increased risk of CVE among patients with and without the history of cardiovascular
diseases, respectively.
Subgroup analyses with adjustments for available data on BMI, systolic blood pressure, LDLcholesterol and total cholesterol at
diagnosis revealed similar risks on cardiovascular outcomes, associated with clinical inertia.
Additional Analyses on the Effects of Glycaemic Burden
Among patients receiving IT before 12 months, those with HbA1c above 7% (53 mmol/mol) and 7.5% (58 mmol/mol) during 1 year
post diagnosis had significantly increased risk of any CVE by 24% (HR CI: 1.11, 1.40) and 33% (HR CI: 1.19, 1.50), respectively
compared to those with HbA1c below 7% (53 mmol/mol) and 7.5% (58 mmol/mol) (). These patients also had significantly
increased risks for MI, HF and stroke. Irrespective of the intensity of antidiabetes drugs and the history of CVD, patients with
HbA1c above 7% (53 mmol/mol) consistently over 1 year post diagnosis had 21% (HR CI: 1.15, 1.28; p < 0.01) increased risk of
composite CVE. Among patients without history of CVD, HbA1c above 7% (53 mmol/mol) was associated with 22% increased risk
for CVE (HR CI: 1.14, 1.29; p < 0.01).
Table 3. Hazard ratios (95% CI) associated with delays in treatment intensification by 1 year in interaction with poor glycaemic
control [HbA1C ≥7% (≥53 mmol/mol) and HbA1C ≥7.5% (≥58 mmol/mol)] consistently during 1 year post diagnosis of diabetes
for cardiovascular events
MI
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.37 (1.09, 1.72) <0.01 1.21 (0.81, 1.82) 0.36 1.32 (1.08, 1.61) <0.01
year
B: IT after 1
1.80 (1.45, 2.22) <0.01 1.34 (0.91, 1.96) 0.13 1.67 (1.39, 2.01) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.59 (1.27, 1.99) <0.01 1.12 (0.73, 1.71) 0.62 1.47 (1.20, 1.79) <0.01
year
B: IT after 1
1.56 (1.24, 1.97) <0.01 1.42 (0.95, 2.14) 0.09 1.52 (1.24, 1.86) <0.01
year
HF
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.14 (0.94, 1.40) 0.19 1.52 (1.09, 2.12) 0.015 1.23 (1.04, 1.46) 0.017
year
B: IT after 1
1.63 (1.36, 1.96) <0.01 1.66 (1.21, 2.27) <0.01 1.64 (1.40, 1.91) <0.01
year
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With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.07, 1.62) <0.01 1.52 (1.08, 2.13) 0.016 1.37 (1.15, 1.63) <0.01
year
B: IT after 1
1.61 (1.32, 1.97) <0.01 1.50 (1.06, 2.12) 0.021 1.58 (1.33, 1.88) <0.01
year
Stroke
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.28 (1.03, 1.60) 0.025 1.80 (1.10, 2.95) 0.019 1.36 (1.12, 1.66) <0.01
year
B: IT after 1
1.50 (1.22, 1.84) <0.01 1.60 (0.98, 2.60) 0.06 1.51 (1.25, 1.83) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.27 (1.01, 1.59) 0.040 1.89 (1.16, 3.06) 0.010 1.36 (1.11, 1.67) <0.01
year
B: IT after 1
1.37 (1.09, 1.71) <0.01 1.34 (0.78, 2.30) 0.28 1.36 (1.11, 1.67) <0.01
year
Any CVE
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.22 (1.07, 1.38) <0.01 1.36 (1.06, 1.74) 0.015 1.24 (1.11, 1.40) <0.01
year
B: IT after 1
1.64 (1.45, 1.85) <0.01 1.57 (1.25, 1.98) <0.01 1.62 (1.46, 1.80) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.15, 1.50) <0.01 1.40 (1.09, 1.81) <0.01 1.33 (1.19, 1.50) <0.01
year
B: IT after 1
1.50 (1.32, 1.71) <0.01 1.50 (1.17, 1.94) <0.01 1.50 (1.33, 1.68) <0.01
year
The reference group was those with TTIT <12 months and HbA1c <7 or 7.5% (<53 or 58 mmol/mol). A: TTIT <12 months and
HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol), B: TTIT ≥12 months and HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol). Analyses are based
on multivariate Coxregression models, with contrast matrix to evaluate the effect of delay in treatment intensification in
conjunction higher and lower levels of HbA1c at 7 and 7.5% cut offs (53 and 58 mmol/mol).
Male patients, current smokers, and patients who developed renal disease during followup had 12, 51, and 43% increased risk of
composite CVE (all p < 0.01), respectively.
Discussion
Our population level study, based on more than 100,000 newly diagnosed T2DM patients with median 5.3 years of followup,
reveals that (1) 26% of patients with HbA1c above 7% (53 mmol/mol) during 2 years post diagnosis of diabetes did not receive
any intensified treatment for hyperglycaemia during followup, (2) 32 and 46% of patients receiving early treatment intensification
within 6 and 12 months of diagnosis continued to have poor glycaemic control over 2 years post diagnosis [HbA1c above 7.5%
(58 mmol/mol)], (3) a 1 year delay in treatment intensification in conjunction with poor glycaemic control significantly increased the
risks of HF, stroke and composite CVE in patients with and without history of CVD before diagnosis of diabetes, and (4)
irrespective of early treatment intensification, the glycaemic burden was significantly associated with increased risk of MI, HF,
stroke and composite CVE.
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In the study cohort 54% never received any intensified treatment, while their average HbA1c level remained above 6.5% (48
mmol/mol), but below 7% (53 mmol/mol), during 2 years post diagnosis (Fig. 1a). In the "never intensified" group, the proportions
of patients with HbA1c consistently above 7% (53 mmol/mol) and 7.5% (58 mmol/mol) during 1/2 years post diagnosis were
15/11% and 7/4%, respectively. The median followup time in this group was 4.7 years. The incidence of any CVE in this group
was 5.5% compared to 8.4% in the IT group.
Earlier observational studies have reported about 3 years of delay in treatment intensification (irrespective of glucose level),[21]
high glycaemic burden [HbA1c >7.5% (>58 mmol/mol)] for over more than 5 years after the addition of a multiple OADs and
insulin,[19,21,34,35] and that it took several years to add insulin after the initiation of 2 OADs.[34] The median (IQR) months to
treatment intensification in our study was 21,[5,44] which is about 12 months less than that reported by Khunti et al..[21] However,
our results are not directly comparable, as the studies were differently designed. In our study those who received IT within 6/12
months of diagnosis had a significant reduction in HbA1c by 2.5/2.3% within 6 and 12 months post diagnosis (Fig. 1b). Our
findings on the failure of intensified treatment to maintain HbA1c within a clinically acceptable limit is broadly in line with those
reported in the large surveys conducted in USA and UK.[36–39] However, as no study has yet reported the trajectory of HbA1c
with treatment intensification, our unique findings are not directly comparable. The mechanisms of increased risk of
macrovascular events with hyperglycaemia are not fully known but may include oxidative stress, inflammation and thrombosis.[40–
42]
The ACCORD study in patients with 10 years of duration of T2DM could not establish any significant benefit of intensified glucose
lowering treatment on macrovascular event during 3.5 years of median followup.[6] However, the meta analyses of four major
cardiovascular outcome trials in patients with T2DM, including the ACCORD trial data, reported a 15–17% risk reduction in MI,
15% risk reduction in coronary heart disease and 9% risk reduction in major cardiovascular event associated with intensive
glucose control therapy.[9,43] While the UKPDS trial was based on newly diagnosed diabetes patients, the median duration of
diabetes in the participants of ACCORD, ADVANCE and VADT trials was 9 years, and 34% of them had history of major
cardiovascular disease before randomisation. Findings of our study based on a cohort of patients with new diagnosis of T2DM is
broadly in line with the findings of the meta analyses in relation to the beneficial effects of intensified glucose lowering treatments
on major cardiovascular risks. The recent cardiovascular outcome trials in established T2DM patients had about 5 years of follow
up and do not provide insight into any longer time benefit in terms of cardiovascular risk. In our cohort with minimum 5 years of
followup (n = 47,161) who continued to have HbA1c above 7% over 1 year, delay in treatment intensification was associated with
65% (95% CI of HR: 1.49, 1.84) increased risk of CVE—very similar to what we observed in the whole cohort with median 5.3
years of followup.
Although early treatment intensification did not reduce the HbA1c below clinically acceptable limit in a significant proportion of
patients, the residual benefit of intensified treatment on macrovascular risk is considerable. Compared to patients with HbA1c
<7% (<53 mmol/mol) during 1 year post diagnosis, those with HbA1c ≥7% (≥53 mmol/mol) and received IT within a year of
diagnosis had 38% lower risk for any CVE (HR: 1.24) compared to those who had delayed treatment intensification (HR: 1.62, ).
Early treatment intensification also showed considerable residual benefits on MI, HF and stroke. This new finding on the residual
benefit of intensive antidiabetes treatment on longterm macrovascular risk, even in patients with continued high glycaemic
burden, needs further evaluations with longer term HbA1c trajectory, and other cardiovascular risk factors.
Table 3. Hazard ratios (95% CI) associated with delays in treatment intensification by 1 year in interaction with poor glycaemic
control [HbA1C ≥7% (≥53 mmol/mol) and HbA1C ≥7.5% (≥58 mmol/mol)] consistently during 1 year post diagnosis of diabetes
for cardiovascular events
MI
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.37 (1.09, 1.72) <0.01 1.21 (0.81, 1.82) 0.36 1.32 (1.08, 1.61) <0.01
year
B: IT after 1
1.80 (1.45, 2.22) <0.01 1.34 (0.91, 1.96) 0.13 1.67 (1.39, 2.01) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
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B: IT after 1
1.56 (1.24, 1.97) <0.01 1.42 (0.95, 2.14) 0.09 1.52 (1.24, 1.86) <0.01
year
HF
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.14 (0.94, 1.40) 0.19 1.52 (1.09, 2.12) 0.015 1.23 (1.04, 1.46) 0.017
year
B: IT after 1
1.63 (1.36, 1.96) <0.01 1.66 (1.21, 2.27) <0.01 1.64 (1.40, 1.91) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.07, 1.62) <0.01 1.52 (1.08, 2.13) 0.016 1.37 (1.15, 1.63) <0.01
year
B: IT after 1
1.61 (1.32, 1.97) <0.01 1.50 (1.06, 2.12) 0.021 1.58 (1.33, 1.88) <0.01
year
Stroke
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.28 (1.03, 1.60) 0.025 1.80 (1.10, 2.95) 0.019 1.36 (1.12, 1.66) <0.01
year
B: IT after 1
1.50 (1.22, 1.84) <0.01 1.60 (0.98, 2.60) 0.06 1.51 (1.25, 1.83) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.27 (1.01, 1.59) 0.040 1.89 (1.16, 3.06) 0.010 1.36 (1.11, 1.67) <0.01
year
B: IT after 1
1.37 (1.09, 1.71) <0.01 1.34 (0.78, 2.30) 0.28 1.36 (1.11, 1.67) <0.01
year
Any CVE
With HbA1C ≥7% (≥53 mmol/mol)
A: IT within 1
1.22 (1.07, 1.38) <0.01 1.36 (1.06, 1.74) 0.015 1.24 (1.11, 1.40) <0.01
year
B: IT after 1
1.64 (1.45, 1.85) <0.01 1.57 (1.25, 1.98) <0.01 1.62 (1.46, 1.80) <0.01
year
With HbA1C ≥7.5% (≥58 mmol/mol)
A: IT within 1
1.32 (1.15, 1.50) <0.01 1.40 (1.09, 1.81) <0.01 1.33 (1.19, 1.50) <0.01
year
B: IT after 1
1.50 (1.32, 1.71) <0.01 1.50 (1.17, 1.94) <0.01 1.50 (1.33, 1.68) <0.01
year
The reference group was those with TTIT <12 months and HbA1c <7 or 7.5% (<53 or 58 mmol/mol). A: TTIT <12 months and
HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol), B: TTIT ≥12 months and HbA1c ≥7 or 7.5% (≥53 or 58 mmol/mol). Analyses are based
on multivariate Coxregression models, with contrast matrix to evaluate the effect of delay in treatment intensification in
conjunction higher and lower levels of HbA1c at 7 and 7.5% cut offs (53 and 58 mmol/mol).
Treatment intensification by insulin and sulfonylurea drugs and its association with cardiovascular and mortality risk was recently
evaluated by Roumie et al..[44] Patients who added insulin to the first line metformin treatment had 30% significantly higher
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evaluated by Roumie et al..[44] Patients who added insulin to the first line metformin treatment had 30% significantly higher
adjusted risk of composite macrovascular events, compared to those who intensified the treatment by adding sulfonylurea to
metformin. In our study about 9% patients received treatment intensification with insulin, and these patients had higher HbA1c at
diagnosis and during followup before intensification, as expected. Patients receiving insulin treatment are generally at higher risk
profile, and the finding from Roumie et al.[44] could be partially attributed to this factor. In this study our focus was on glycaemic
burden and the failure to intensify antihyperglycaemic treatment when deemed necessary. We do however recognise the
importance of evaluating therapeutic inertia in a holistic way including cardiovascular risk burden. In our risk analyses, we have
adjusted for the use of cardioprotective medications (including antihypertensive and lipid lowering drugs) and the risk of renal
diseases. We also conducted separate analyses adjusting for available cardiovascular risk factors (weight, blood pressure and
cholesterol) in 62,000 patients.
While MI and stroke are relatively well defined hard outcomes with acute onset, HF is a disease of slow onset which develops
over time. This introduces the difficulty in defining a correct time of onset, and the likelihood of getting HF detected in the setting
of primary care database to a great extent depends on medical attention and on the number of encounters with general
practitioners. To account for possible detection bias in this context, we conducted additional analyses with HF confirmed by
electrocardiogram analyses, resulting in similar risk estimates for both events.
Patientlevel data from electronic databases present challenges in terms of accuracy and completeness of the study variables of
interest. The limitations of this study include: (1) the time to treatment intensification was based on the dates of available
prescriptions longitudinally, with the likelihood of missing data; (2) nonavailability of adherence data on medications; (3) non
availability of prescription on diet and exercise; (4) failure to account for the socioeconomic status of the patients, which may well
be associated with poor glycaemic control and with an elevated risk of cardiovascular diseases; (5) nonavailability of complete
and reliable data on alcohol consumption; (6) nonavailability of complete and reliable longitudinal data on doses for individual
medications, (7) nonavailability of hospitalisation data for MI and stroke, and (8) the potential for residual confounding, as
common in any clinical epidemiological study. Due to lack of data on longitudinal doses of individual antidiabetes medications, we
could not consider the dose escalation for some antidiabetes therapies as potential treatment intensification. However, these
issues are unlikely to affect the robustness of the results of this study. The large analysis cohort was selected from the validated
CPRD database should be considered as a representative sample, and as such, provides a good picture of the state of diabetes
control in routine practice. Apart from complete data on demographics, we had complete data on HbA1c measured within 3month
window of diagnosis of diabetes. The 6monthly followup measures of HbA1c were imputed for only 9% missing cases with
random missing pattern. Finally, careful design of the study by defining sensible exposure time, time line for events, and
appropriate adjustments for various aspects while determining the timetoevents are the primary strengths of the study.
Conclusions
As with all observational studies, we were unable to provide definitive evidence for direct cause–effect relationships, and the risks
of false positive or negative findings due to selection bias and residual confounding, even after the most stringent corrections,
may not be trivial. However, although the results from large controlled clinical trials evaluating the effect of intensified glucose
lowering treatment on macrovascular complications in patients with T2DM have been inconclusive, our longitudinal study with
primary care level data demonstrates the beneficial effect of guideline recommended tight glycaemic targets on longterm
cardiovascular risks.
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Abbreviations
ADD: antidiabetes drug, BMI: Body mass index, CI: confidence interval, CPRD: Clinical Practice Research Database, CVE:
macrovascular event, HbA1c: haemoglobin A1c, HF: heart failure, HR: hazard ratio, INS: insulin
, IT: treatment intensification, MI: myocardial infarction, OAD: oral antidiabetes drug, OR: odds ratio, T2DM: type 2 diabetes, TTIT:
time to treatment intensification
Acknowledgements
The QIMR Berghofer Medical Research Institute is grateful for support from UKCPRD, Novo Nordisk A/S and an infrastructure
research grant from the Australian Government Department of Education's National Collaborative Research Infrastructure
Strategy initiative through Therapeutic Innovation Australia. The Leicester Diabetes Research Centre, University of Leicester is
grateful for support from the NIHR Collaboration for Leadership in Applied Health Research and Care East Midlands (CLAHRC
EM). The interpretation and conclusions contained in this study are those of the authors alone.
Compliance with ethical guidelines
Cardiovasc Diabetol. 2015;14(100) © 2015 BioMed Central, Ltd.
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